The condition of being overweight or obese has been implicated as a risk factor for hepatocellular carcinoma. Hepatocellular carcinoma (HCC) risk is 1.68 in men, HCC is associated with the highest relative-risk increase as a consequence of obesity compared to all the cancers studied including prostate, kidney, gallbladder, colon, rectum, esophagus, stomach and pancreas. Considering the pandemic nature of obesity (approximately two-thirds of US adults are overweight or obese), a 1.68 - 4.52 fold increase in relative liver cancer risk is a very significant medical problem. There is a clear and compelling need to develop chemopreventive strategies to combat HCC in obese population. The major goal of this proposal is to develop effective chemopreventive strategies to target HCC in obese state. We will elucidate the molecular mechanism(s) by which Honokiol, a bioactive compound derived from Magnolia species, prevents HCC growth in obese hyperleptinemic conditions. We and others have shown that high leptin levels (hyperleptinemia) associated with obesity is a major driver of HCC progression and metastasis. Thus, prevention of the neoplastic-effects of leptin is imminent and important area of research. Investigating bioactive approaches to block leptin signaling, we recently discovered that honokiol can effectively reduce leptin-induced proliferation and migration of HCC cells. The project consists of two highly innovative aims. Aim 1 will examine whether honokiol blocks leptin-induced epithelial-mesenchymal transition, inhibits leptin-signaling network and investigate the role of miR-122 in mediating honokiol actions. Results from these studies will establish honokiol as a novel and effective leptin-antagonist and dissect the underlying molecular interactions between honokiol and leptin signaling axes potentially revealing new crosstalk. Aim 2 will examine whether honokiol block paracrine actions of leptin and effectively prevents HCC in hyperleptinemic obese state. Preliminary data show that the paracrine effect of leptin plays an important role in adipocytes-HCC cells crosstalk which leads to increased EMT, invasion and migration of HCC cells. Results from this aim will reveal whether honokiol blocks the paracrine effects of leptin and prevent adipocytes-HCC cells crosstalk outcome. Our studies will advance the honokiol chemoprevention field in a new direction showing the effectiveness of honokiol in preventing HCC progression in obese-hyperleptinemic-state and establishing honokiol as a novel leptin-antagonist. These studies will provide pre-clinical information to design clinical trials of honokiol-based chemopreventive strategies for obese persons at high risk for developing HCC. It is important to note that obesity is attributed to ~100,000 cancer-related deaths per year in the USA. Additionally, our studies will also show the effectiveness of honokiol in preventing HCC in non-obese conditions therefore our findings will have far-reaching impact.